CN104768965A - C17-heteroaryl derivatives of oleanolic acid and methods of use thereof - Google Patents

Abstract

Disclosed herein are novel C17-heteroaryl derivatives of oleanolic acid, including those of formula (I): where variables are defined in this text. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising the compounds. Also provided are methods and intermediates useful in the preparation of the compounds, as well as methods of using the compounds as, for example, anti-oxidative modulators of inflammation and compositions using the compounds.

Description

C17-heteroaryl derivatives of oleanolic acid and methods of use thereof

This application claims the benefit of U.S. Provisional Patent Application No. 61/699,199, filed September 10, 2012, which is hereby incorporated by reference in its entirety.

Pursuant to 37 C.F.R.1.821(c), the Sequence Listing is hereby filed in an ASCII text file named "REATP0076US_SequenceListing_ST25.txt (REATP0076US_Sequence Listing_ST25.txt)" dated September 9, 2013 created and has a size of about 1KB. The entire contents of the aforementioned documents are hereby incorporated by reference.

Background technique

I.Technical field

The present invention relates generally to the fields of biology and medicine. More specifically, the present invention relates to compounds, compositions and methods for the treatment and prevention of diseases, such as those associated with oxidative stress and inflammation.

II. Description of related technologies

The anti-inflammatory and anti-proliferative activities of the naturally occurring triterpenoid oleanolic acid have been improved through chemical modification. For example, 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid (CDDO) and related compounds have been developed (Honda et al., 1997; Honda et al. Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda, et al., 2002; Suh et al., 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005 and US Patents 8,129,429, 7,915,402, 8,124,799, 8,071,632, 8,338,618, and 7,943,778). The methyl ester, bardoxolone methyl (CDDO-Me), has been evaluated clinically in the treatment of cancer and chronic kidney disease (Pergola et al., 2011; Hong et al., 2012).

Synthetic triterpenoid analogues of oleanolic acid have also been shown to be inhibitors of cellular inflammatory processes such as inducible nitric oxide synthase (INS) via IFN-γ in mouse macrophages ( iNOS) and COX-2 induction. See Honda et al. (2000a); Honda et al. (2000b) and Honda et al. (2002). Synthetic derivatives of another triterpenoid betulinic acid have also been shown to inhibit cellular inflammatory processes, although not extensively characterized (Honda et al., 2006). The pharmacology of these synthetic triterpenoid molecules is complex. Compounds derived from oleanolic acid have been shown to affect the function of various protein targets and thus modulate the activity of several important cell signaling pathways related to oxidative stress, cell cycle control and inflammation (e.g., Dinkova-Kostova et al., 2005 ; Ahmad et al., 2006; Ahmad et al., 2008; Liby et al., 2007a). Although betulinic acid derivatives have shown comparable anti-inflammatory properties, their pharmacology also appears to be significantly different compared to OA-derived compounds (Liby et al., 2007b). Considering that the spectrum of biological activities of known triterpenoid derivatives is variable, and in view of the diversity of diseases that can be treated or prevented by compounds with potent antioxidant and anti-inflammatory effects and the diversity of diseases A high unmet medical need represents a need for the synthesis of novel compounds of different structures that may have an improved spectrum of biological activity for the treatment of one or more indications.

Contents of the invention

The present disclosure provides novel synthetic triterpenoid derivatives having anti-inflammatory and/or antioxidant properties, pharmaceutical compositions and methods of their manufacture and methods of their use.

In one aspect, there is provided a compound of the formula: or a pharmaceutically acceptable salt thereof:

in:

n is 0-3;

Ar is heteroaryldiyl _(C≤8) or a substituted form thereof; and

Y is:

hydrogen, hydroxy, halo, amino or cyano or –NCO; or

Alkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤8) , Heterocycloalkyl _(C≤12) , acyl _(C≤12) , alkoxy _(C≤8) , aryloxy _(C≤12) , acyloxy _(C≤8) , alkylamino _{(C≤ 8)} , dialkylamino _(C≤8) , arylamino _(C≤8) , aralkylamino _(C≤8) , alkylthio _(C≤8) , acylthio _(C≤8) , Alkylsulfonylamino _(C≤8) or substituted forms of any of these groups.

In some embodiments, Y is -H. In some embodiments, Y is alkyl _(C≤4) , such as methyl, n-propyl, isopropyl, or cyclopropyl. In some embodiments, Y is substituted alkyl _(C≤4) , such as methoxymethyl.

In some embodiments, Ar is

In some embodiments, n=0. In other embodiments, n=1.

In some embodiments, the compound is selected from the group consisting of:

Or a pharmaceutically acceptable salt of any one of the above formulas.

In some aspects, pharmaceutical compositions comprising one or more of the compounds described above and an excipient are provided. In other aspects there is provided a method of treating and/or preventing a disease or condition in a patient in need thereof comprising administering to said patient one or more of the compounds described above in an amount sufficient to treat and/or prevent said disease or condition.

Other objects, features and advantages of the present disclosure will be apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments of the invention, are given by way of example only, since this detailed description will become apparent to those skilled in the art that are within the spirit and scope of the invention. Various changes and modifications. Note that just because a particular compound belongs to one particular formula does not mean it cannot also belong to another formula.

Detailed ways

Disclosed herein are novel compounds and compositions having antioxidant and/or anti-inflammatory properties, methods of their manufacture, and methods of their use, including methods for treating and/or preventing disease.

I. Definition

When used in the context of chemical groups: "hydrogen" means -H; "hydroxyl" means -OH; "oxo" means =O; "carbonyl" means -C( =O)-; "Carboxy" means -C(=O)OH (also written as -COOH or _-CO2H ); "halo" means independently -F, -Cl, -Br or -I;"Amino" means _-NH2 ; "hydroxyamino" means -NHOH; "nitro" means _-NO2 ; imino means =NH; "cyano" means -CN; "isocyanate" means - N=C=O; "azido" means _-N3 ; in a monovalent context, "phosphate" means -OP(O)(OH) ₂ or its deprotonated form; in a divalent context , "phosphate" means -OP(O)(OH)O- or its deprotonated form; "mercapto" means -SH; and "thio" means =S;""Sulfonyl" means -S(O) _2- ; and "sulfinyl" means -S(O)-.

In the context of a chemical formula, the symbol "-" means a single bond, "=" means a double bond, and "≡" means a triple bond. The symbol "----" represents an optional bond which, if present, is a single or double bond. symbol Represents a single or double bond. So, for example, the formula include and And it is to be understood that no one of said ring atoms forms part of more than one double bond. Furthermore, it should be noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when one or two stereogenic atoms are attached. Rather, it encompasses all stereoisomers as well as mixtures thereof. When drawn perpendicular to a bond (e.g., for a methyl group, ),symbol Indicates the point of attachment of the group. It should be noted that for larger groups, the point of attachment is usually only identified in this way to help the reader clearly identify the point of attachment. symbol Means a single bond where the group attached to the butt end of the wedge is located "off the paper". symbol Means a single bond where the group attached to the butt end of the wedge is located "in the plane of the paper". symbol Means a single bond in which the geometry (eg, E or Z) surrounding the double bond is undefined. Both options and combinations thereof are therefore contemplated. When one of the atoms linked by the bond is a metal atom (M), the above bond order is not restrictive. In such cases, it is understood that the actual bonding may contain significant multiple bonding and/or ionic character. Therefore, unless otherwise indicated, the formulas MC, M=C, M----C and Both refer to bonds of any type and order between metal atoms and carbon atoms. Any undefined valences on atoms of structures shown in this application implicitly represent hydrogen atoms bonded to said atoms. A thick dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.

When the group "R" is depicted as a "floating group" on a ring system in the following formulae:

R can replace any hydrogen atom attached to any ring atom, including depicted hydrogen, implied hydrogen, or explicitly defined hydrogen, so long as a stable structure results. When the group "R" is depicted as a "floating group" on a fused ring system in the following formulae:

Unless otherwise stated, R can replace any hydrogen attached to any ring atom of any fused ring. Alternative hydrogens include depicted hydrogens (e.g., hydrogens attached to nitrogen in the above formulas), implicit hydrogens (e.g., hydrogens not shown in the above formulas but understood to be present), explicitly defined hydrogens and optional hydrogens whose presence depends on the identity of the ring atoms (eg, hydrogen attached to group X when X equals -CH-), so long as a stable structure results. In the depicted example, R can be located on a 5- or 6-membered ring of the fused ring system. In the above formulas, the subscript "y" immediately following the group "R" in parentheses represents a numerical variable. Unless otherwise stated, this variable can be 0, 1, 2 or any integer greater than 2, limited only by the maximum number of replaceable hydrogen atoms of the ring or ring system.

For the groups and classes below, the subscripts in parentheses further define the group/class as follows: "(Cn)" defines the exact number (n) of carbon atoms in the group/class. "(C≤n)" defines the maximum number (n) of carbon atoms that can be in the group/class, the minimum number is as small as possible for the group in question, e.g., it should be understood that the group " The minimum number of carbon atoms in an "alkenyl _(C≤8) " or class "alkene _(C≤8) " is 2. For example, "alkoxy _(C≦10) " indicates those alkoxy groups having 1 to 10 carbon atoms. (Cn-n') defines the minimum number (n) and maximum number (n') of carbon atoms in the group. Similarly, "alkyl _(C2-10) " indicates those alkyl groups having 2 to 10 carbon atoms.

Unless stated below, the term "saturated" as used herein means that such modified compound or group has no carbon-carbon double bonds and no carbon-carbon triple bonds. In the case of substituted forms of saturated groups, one or more carbon-oxygen or carbon-nitrogen double bonds may be present. And when said linkages are present, carbon-carbon double bonds which may occur as part of keto-enol tautomerization or imine/enamine tautomerization are not excluded.

When used without the "substituted" modifier, the term "aliphatic" means that such modified compound/group is a hydrocarbon or group that is acyclic or cyclic but not aromatic. In an aliphatic compound/group, carbon atoms may be bonded together in straight chains, branched chains or non-aromatic rings (cycloaliphatic). Aliphatic compounds/groups may be saturated, i.e. bonded by a single bond (alkane/alkyl), or unsaturated, with one or more double bonds (alkene/alkenyl) or with one or more triple bonds ( alkyne/alkynyl).

When used without the "substituted" modifier, the term "alkyl" refers to a structure having a carbon atom as the point of attachment, having a straight or branched chain, cyclic, cyclic, or acyclic And a monovalent saturated aliphatic group having no atoms other than carbon and hydrogen. Thus, a cycloalkyl group, as used herein, is a subgroup of an alkyl group wherein the carbon atom forming the point of attachment is also a member of one or more non-aromatic ring structures, wherein the cycloalkyl group consists of no atoms other than carbon and hydrogen. The term as used herein does not exclude the presence of one or more alkyl groups (carbon number limitations permitted) attached to a ring or ring system. Groups -CH ₃ (Me (methyl)), -CH ₂ CH ₃ (Et (ethyl)), -CH ₂ CH ₂ CH ₃ (n-Pr (n-propyl) or propyl), -CH ( CH ₃ ) ₂ (i-Pr, ⁱ Pr or isopropyl), -CH(CH ₂ ) ₂ (cyclopropyl), -CH ₂ CH ₂ CH ₂ CH ₃ (n-Bu(n-butyl)), -CH(CH ₃ )CH ₂ CH ₃ (sec-butyl), -CH ₂ CH(CH ₃ ) ₂ (isobutyl), -C(CH ₃ ) ₃ (tert-butyl, t-butyl, t- Bu or ^tBu ), —CH ₂ C(CH ₃ ) ₃ (neopentyl), cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl are non-limiting examples of alkyl groups. When used without the "substituted" modifier, the term "alkanediyl" means having one or two saturated carbon atoms as points of attachment, having a straight or branched chain, cyclic, cyclic A divalent saturated aliphatic group having an or acyclic structure, no carbon-carbon double or triple bond, and no atoms other than carbon and hydrogen. The groups -CH ₂ -(methylene), -CH ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, and is a non-limiting example of an alkanediyl group. When used without the "substituted" modifier, the term "alkylidene" refers to the divalent group =CRR', where R and R' are independently hydrogen, alkyl, or R Together with R' represents an alkanediyl group having at least two carbon atoms. Non-limiting examples of alkylene include: =CH ₂ , =CH(CH ₂ CH ₃ ), and =C(CH ₃ ) ₂ . "Alkane" refers to the compound HR, wherein R is alkyl, as that term is defined above. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted. The following groups are non-limiting examples of substituted alkyl groups: _-CH2OH , _-CH2Cl , _-CF3 , _-CH2CN , _-CH2C (O)OH, _-CH2C (O) OCH ₃ , -CH ₂ C(O)NH ₂ , -CH ₂ C(O)CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OC(O)CH ₃ , -CH ₂ NH ₂ , -CH ₂ N( _{CH3 ) 2} and _-CH2CH2Cl . The term "haloalkyl" is a subgroup of substituted alkyl groups in which one or more hydrogen atoms have been replaced by a halo group and no atoms other than carbon, hydrogen and halogen are present. The group _-CH2Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subgroup of substituted alkyl groups in which one or more hydrogens have been replaced by a fluoro group and no atoms other than carbon, hydrogen and fluorine are present. The groups _-CH2F , _-CF3 and _-CH2CF3 are non _- limiting examples of fluoroalkyl groups.

When used without the "substituted" modifier, the term "alkenyl" refers to a structure having a carbon atom as the point of attachment, having a straight or branched chain, cyclic, cyclic or acyclic structure , a monovalent unsaturated aliphatic group having at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: -CH= _CH2 (vinyl), -CH=CHCH3, -CH= _CHCH2CH3 , -CH2CH _{= CH2 (} allyl ₎ , _-CH2CH =CHCH3 and -CH=CHCH _{= CH2} . When used without the "substituted" modifier, the term "alkenediyl" means having two carbon atoms as the point of attachment, having a straight or branched chain, cyclic, cyclic A divalent unsaturated aliphatic group having at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen, or acyclic structure. The groups -CH=CH-, -CH=C(CH ₃ )CH ₂ -, -CH=CHCH ₂ - and is a non-limiting example of alkenediyl. It should be noted that although alkenediyl is aliphatic, once it is attached at both ends, this does not preclude this group from forming part of an aromatic structure. The term "alkene or olefin" is synonymous and refers to a compound of formula HR, wherein R is alkenyl, as that term is defined above. "Terminal olefin" refers to an olefin having only one carbon-carbon double bond, where the bond forms a vinyl group at one end of the molecule. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted. The groups -CH=CHF, -CH=CHCl and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

When used without the "substituted" modifier, the term "alkynyl" refers to a structure having a carbon atom as the point of attachment, having a straight or branched chain, cyclic, cyclic, or acyclic , a monovalent unsaturated aliphatic radical having at least one carbon-carbon triple bond and having no atoms other than carbon and hydrogen. The term alkynyl as used herein does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, _-C≡CCH3 , and _-CH2C≡CCH3 are non _- limiting examples of alkynyl groups. "Alkyne" refers to a compound HR wherein R is alkynyl. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted.

When used without the "substituted" modifier, the term "aryl" refers to a monovalent unsaturated aromatic radical having, as the point of attachment, aromatic carbon atoms forming one or more six-membered aromatic rings Part of a structure in which the ring atoms are all carbon and in which the group is composed of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. The term as used herein does not exclude the presence of one or more alkyl or aralkyl groups (carbon number limitations permitted) attached to the first aromatic ring or any additional aromatic rings present. Non _- limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, _{-C6H4CH2CH3 (} ethylphenyl ₎ , naphthyl and those derived from biphenyl monovalent group. When used without the "substituted" modifier, the term "arenediyl" refers to a divalent aromatic radical having as points of attachment two aromatic carbon atoms forming one or Part of a plurality of six-membered aromatic ring structures in which the ring atoms are all carbon and in which the monovalent group consists of no atoms other than carbon and hydrogen. The term as used herein does not exclude the presence of one or more alkyl, aryl or aralkyl groups (carbon number limitations permitted) attached to the first aromatic ring or any additional aromatic rings present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be attached by one or more of: a covalent bond, an alkanediyl, or an alkenediyl group (carbon number restrictions are allowed). Non-limiting examples of aryldiyl groups include:

"Aromatic hydrocarbon" means a compound HR wherein R is aryl, as that term is defined above. Benzene and toluene are non-limiting examples of aromatics. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted.

When used without the "substituted" modifier, the term "aralkyl" refers to the monovalent group -alkanediyl-aryl, wherein the terms alkanediyl and aryl are each defined in the same order as provided above. The definitions are used in a consistent manner. Non-limiting examples of aralkyl are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the "substituted" modifier, one or more hydrogen atoms from the alkanediyl and/or aryl have been replaced by -OH, -F, -Cl, - Br, -I, -NH ₂ , -NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(O)NH ₂ , -OC(O)CH ₃ or -S(O) ₂ NH ₂ are independently substituted. Non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-eth-1-yl.

When used without the "substituted" modifier, the term "heteroaryl" refers to a monovalent aromatic group having as a point of attachment an aromatic carbon or nitrogen atom forming one or Part of a plurality of aromatic ring structures in which at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the heteroaryl group does not consist of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. The term as used herein does not exclude the presence of one or more alkyl, aryl and/or aralkyl groups (carbon number limitations permitted) attached to an aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl include furyl, imidazolyl, indolyl, indazolyl (Im), iso Azolyl, picoline, Azolyl, phenylpyridyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl and tri Azolyl. The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as the point of attachment. When used without the "substituted" modifier, the term "heteroaryldiyl" refers to a group having two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as two A divalent aromatic group at the point of attachment, said atom forming part of one or more aromatic ring structures, wherein at least one ring atom is nitrogen, oxygen or sulfur, and wherein said divalent group is not composed of carbon, hydrogen, aromatic Atoms other than nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be attached by one or more of: a covalent bond, an alkanediyl, or an alkenediyl group (carbon number restrictions are allowed). The term as used herein does not exclude the presence of one or more alkyl, aryl and/or aralkyl groups (carbon number limitations permitted) attached to an aromatic ring or aromatic ring system. Non-limiting examples of heteroardiyls include:

"Heteroaryl" refers to compounds HR wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroaromatics. When these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , _-NO2 , - CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted.

When used without the "substituted" modifier, the term "heterocycloalkyl" refers to a monovalent non-aromatic group having a carbon or nitrogen atom as the point of attachment which forms a or part of a plurality of non-aromatic ring structures wherein at least one ring atom is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group does not consist of atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused. The term as used herein does not exclude the presence of one or more alkyl groups (carbon number limitations permitted) attached to a ring or ring system. Furthermore, the term does not exclude the presence of one or more double bonds in a ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl , tetrahydropyranyl, pyranyl, oxiranyl and oxetanyl. The term "N-heterocycloalkyl" refers to a heterocycloalkyl group having a nitrogen atom as the point of attachment. When used without the "substituted" modifier, the term "heterocycloalkanediyl" refers to a compound having two carbon atoms, two nitrogen atoms, or a carbon atom and a nitrogen atom as two points of attachment. A divalent cyclic group, said atoms forming part of one or more ring structures, wherein at least one ring atom is nitrogen, oxygen or sulfur, and wherein said divalent group is not composed of carbon, hydrogen, nitrogen, oxygen and Composition of atoms other than sulfur. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be attached by one or more of: a covalent bond, an alkanediyl, or an alkenediyl group (carbon number restrictions are allowed). The term as used herein does not exclude the presence of one or more alkyl groups (carbon number limitations permitted) attached to a ring or ring system. Furthermore, the term does not exclude the presence of one or more double bonds in a ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkanediyl include:

When these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , _-NO2 , - CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(O)NH ₂ , -OC(O)CH ₃ , -S(O) ₂ NH ₂ or -C(O)OC(CH ₃ ) ₃ (tert-butoxycarbonyl, BOC) independently replace .

When used without the "substituted" modifier, the term "acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, aryl, aralkyl, or heteroaryl, those terms as defined above. Groups -CHO, -C(O)CH ₃ (acetyl, Ac), -C(O)CH ₂ CH ₃ , -C(O)CH ₂ CH ₂ CH ₃ , -C(O)CH(CH ₃ ) ₂ , -C(O)CH(CH ₂ ) ₂ , -C(O)C ₆ H ₅ , -C(O)C ₆ H ₄ CH ₃ , -C(O)CH ₂ C ₆ H ₅ , - C(O)(imidazolyl) is a non-limiting example of an acyl group. "Thioacyl" is defined in a similar manner, except that the oxygen atom of the group -C(O)R has been replaced by a sulfur atom (-C(S)R). The term "aldehyde" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced by a -CHO group. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms (including those directly attached to a carbonyl or thiocarbonyl group, if any) have been replaced by -OH , -F, -Cl, -Br, -I, -NH ₂ , -NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C (O) _CH3 , _-NHCH3 , -NHCH2CH3, -N( _{CH3 ) 2} , -C(O) _NH2 , -OC(O) _CH3 , or -S ₍ O _{) 2NH2} independently substitute. The group -C(O)CH ₂ CF ₃ , -CO ₂ H (carboxy), -CO ₂ CH ₃ (methylcarboxy), -CO ₂ CH ₂ CH ₃ , -C(O)NH ₂ (carbamoyl ) and -CON( _CH3 ) ₂ are non-limiting examples of substituted acyl groups.

When used without the "substituted" modifier, the term "alkoxy" refers to the group -OR, where R is alkyl, as that term is defined above. Non-limiting examples of alkoxy groups include: -OCH ₃ (methoxy), -OCH ₂ CH ₃ (ethoxy), -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ (isopropoxy ), -O(CH ₃ ) ₃ (tert-butoxy), -OCH(CH ₂ ) ₂ , -O-cyclopentyl and -O-cyclohexyl. When used without the "substituted" modifier, the terms "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", ""Heterocycloalkoxy" and "acyloxy" refer to a group defined as -OR, where R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl and acyl, respectively. The term "alkoxydiyl" refers to the divalent group -O-alkanediyl-, -O-alkanediyl-O- or -alkanediyl-O-alkanediyl-. When used without the "substituted" modifier, the terms "alkylthio" and "acylthio" refer to the group -SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced by a hydroxyl group. The term "ether" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced by an alkoxy group. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted.

When used without the "substituted" modifier, the term "alkylamino" refers to the group -NHR, where R is alkyl, as that term is defined above. Non-limiting examples _of alkylamino include: _-NHCH3 and _-NHCH2CH3 . When used without the "substituted" modifier, the term "dialkylamino" refers to the group -NRR', where R and R' can be the same or different alkyl groups or R and R' can be Together they represent alkanediyl. Non-limiting examples of dialkylamino include: -N(CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), and N-pyrrolidinyl. When used without the "substituted" modifier, the terms "alkoxyamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", ""Heteroarylamino","Heterocycloalkylamino", and "Alkylsulfonylamino" means a group defined as -NHR, where R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, respectively radical, heteroaryl, heterocycloalkyl and alkylsulfonyl. A non-limiting example of arylamino is -NHC ₆ H ₅ . When used without the "substituted" modifier, the term "amido" (acylamino) refers to the group -NHR, where R is acyl, as that term is defined above. A non-limiting example of an amide group is -NHC(O) _CH3 . When used without the "substituted" modifier, the term "alkylimino" refers to the divalent group =NR, where R is alkyl, as that term is defined above. The term "alkylaminodiyl" refers to the divalent group -NH-alkanediyl-, -NH-alkanediyl-NH- or -alkanediyl-NH-alkanediyl-. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted. The groups -NHC(O) _OCH3 and -NHC(O) _NHCH3 are non-limiting examples of substituted amido groups.

When used without the "substituted" modifier, the terms "alkylsulfonyl" and "alkylsulfinyl" refer to the groups -S(O ₎ 2R and -S(O)R, respectively , wherein R is alkyl, as the term is defined above. The terms "alkenylsulfonyl", "alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl" and "heterocycloalkylsulfonyl" are used in a similar fashion Defined. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted.

When used without the "substituted" modifier, the term "alkylphosphate" refers to the group -OP(O)(OH)(OR), where R is alkyl, as defined above terms of. Non-limiting examples of alkyl phosphate groups include: -OP(O)(OH)(OMe) and -OP(O)(OH)(OEt). When used without the "substituted" modifier, the term "dialkylphosphate" refers to the group -OP(O)(OR)(OR'), where R and R' may be the same Or different alkyl groups or R and R' can be combined to represent alkanediyl. Non-limiting examples of dialkylphosphate groups include: -OP(O)(OMe) ₂ , -OP(O)(OEt)(OMe), and -OP(O)(OEt) ₂ . When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, _-NH2 , - NO ₂ , -CO ₂ H, -CO ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(O)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N (CH ₃ ) ₂ , —C(O)NH ₂ , —OC(O)CH ₃ , or —S(O) ₂ NH ₂ are independently substituted.

The word "a/an (one)", when used in conjunction with the term "comprising" in the claims and/or specification, may mean "one", but it is also used in conjunction with "one or more", "at least one " and "one or more than one" have the same meaning.

Throughout this application, the term "about" is used to indicate that a value includes variation in the inherent error of the device, method, or variation that exists between study subjects used to determine the value.

"Chiral auxiliary" as used herein refers to a removable chiral group capable of affecting the stereoselectivity of a reaction. Those skilled in the art are familiar with such compounds, and many are commercially available.

The terms "comprise", "have" and "include" are open linking verbs. Any form or tense of one or more of these verbs, such as "singular (comprises/has/includes)", "comprising/having/including", is also open-ended. For example, any method that "comprises," "has/comprises," or "includes" one or more steps is not limited to having only those one or more steps and also encompasses other unlisted steps.

When the term "effective" is used in the specification and/or claims, the term means sufficient to achieve a desired, intended or desired result. "Effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" when used in the context of treating a patient or subject with a compound means sufficient to achieve said The amount of the compound for the treatment of the disease.

The term " _IC50 " as used herein refers to the inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is required to inhibit a given biological, biochemical, or chemical process (or a component of a process, that is, an enzyme, cell, cell receptor, or microorganism) by half .

An "isomer" of a first compound is an individual compound that each molecule contains the same constituent atoms as the first compound, but differs in the configuration of those atoms in three dimensions.

The term "patient" or "subject" as used herein refers to a living mammalian organism such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, adolescents, infants and fetuses.

As generally used herein, "pharmaceutically acceptable" refers to those substances suitable for use in contact with tissues, organs and/or body fluids of humans and animals without undue toxicity, irritation, allergic response within the scope of sound medical judgment. or other problems or complications, compounds, materials, compositions and/or dosage forms commensurate with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable salt" means a salt of a compound of the present invention which is pharmaceutically acceptable as defined above and which possesses the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as 1,2-ethanediol Sulfonic acid, 2-hydroxyethylsulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methyl Bicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, Cinnamic acid, citric acid, cypionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, caproic acid, hydroxynaphthoic acid, lactic acid, dodecane Sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl substituted alkanoic acid, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, etc. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It will be appreciated that the particular anion or cation which forms part of any salt of the invention is not critical so long as the salt as a whole is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and methods of their preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (eds. P.H. Stahl and C.G. Wermuth, Verlag Helvetica Chimica Acta, 2002).

The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle involved in the delivery or delivery of a chemical agent, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.

"Prevention or preventing" includes: (1) inhibiting the onset of a disease in a subject or patient who may be at risk and/or susceptible to the disease but has not yet experience or exhibit any or all of the pathology or symptoms of the disease; and/or (2) slow down the onset of the pathology or symptoms of the disease in a subject or patient who may have At risk of and/or predisposed to developing the disease, but not having experienced or exhibited any or all of the pathology or symptoms of the disease.

"Prodrug" means a compound which can be converted metabolically in vivo into an inhibitor according to the invention. Prodrugs themselves may or may not be active against a given target protein. For example, a compound containing a hydroxy group can be administered as an ester that is converted to the hydroxy compound by in vivo hydrolysis. Suitable esters that can be converted to hydroxy compounds in vivo include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, Ester, fumarate, maleate, methylene-bis-beta-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyl tartrate, methanesulfonic acid Esters, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclamate, quinate, amino acid ester, etc. Similarly, compounds containing amine groups can be administered as amides that are converted to amine compounds by in vivo hydrolysis.

"Stereoisomers" or "optical isomers" are isomers of a given compound in which the same atoms are bonded to the same other atoms, but differ in the configuration of those atoms in three dimensions. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left and right hands. "Diastereoisomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also known as a stereocenter or stereogenic center, which is any point in a molecule with a band such that the interchange of any two groups results in a stereogenic center. isomer groups, but the points need not be atoms. In organic compounds, the chiral center is usually a carbon, phosphorus, or sulfur atom, although in organic and inorganic compounds other atoms may also be stereocenters. Molecules can have multiple stereocenters, giving them many stereoisomers. In compounds where stereoisomerism is due to a tetrahedral stereogenic center (eg, tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry generally have less than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, the mixture of enantiomers may be enantiomerically enriched such that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that for any stereocenter or axis of chirality for which the stereochemistry has not been defined, that stereocenter or axis of chirality may exist in its R form, in its S form, or as a mixture of said R and S forms, including racemic and a non-racemic mixture. The phrase "substantially free of other stereoisomers" as used herein means that the composition contains ≤ 15%, more preferably ≤ 10%, even more preferably ≤ 5% or most preferably ≤ 1% of other stereoisomers body.

"Treatment or treating" includes (1) inhibiting the disease in a subject or patient who is experiencing or exhibiting the pathology or symptoms of the disease (eg, preventing the further development of the pathology and/or symptoms), ( 2) ameliorating the disease in a subject or patient experiencing or exhibiting the pathology or symptoms of the disease (e.g., reversing the pathology and/or symptoms), and/or (3) effectuating the pathology or symptoms of the disease Any measurable decrease in the disease in a subject or patient with or symptoms.

Other abbreviations used herein are as follows: DMSO, dimethyl sulfoxide; (COCl) ₂ , oxalyl chloride; EtN ₃ or TEA, triethylamine; DMAP, dimethylaminopyridine; Et ₂ O, diethyl ether; ₂ , hydrazine butyrate; i-PrCONHNH ₂ , hydrazine isobutyrate; c-PrCONHNH ₂ , hydrazine cyclopropanecarboxylate; p-TsOH, p-toluenesulfonic acid; DMF, dimethylformamide; EDCl, 1-ethyl- 3-(3-Dimethylaminopropyl)carbodiimide; NO, nitric oxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; FBS, fetal bovine serum; IFNγ or IFN-γ, interferon-γ; TNFα or TNF-α, tumor necrosis factor α; IL-1β, interleukin-1β; HO-1, inducible heme oxygenase.

The above definitions supersede any conflicting definitions in any references incorporated herein by reference. However, the fact that certain terms are defined should not be taken as indicating that any undefined term is indeterminate. Rather, all terms used are considered to describe the invention clearly enough to enable one skilled in the art to understand the scope and practice the invention.

II. COMPOUNDS AND SYNTHESIS METHODS

Compounds provided by this disclosure are shown in the Summary above, in the Claims and in the sections below. They can be prepared using the methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry applied by those skilled in the art. The principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

The compounds of the present invention may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be isolated in optically active or racemic form. Accordingly, all chiral, diastereomeric, racemic, epimeric and all geometric isomeric forms of a formula are intended unless the specific stereochemistry or isomeric form is expressly indicated of. The compounds may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the invention can have either the S configuration or the R configuration.

The chemical formulas used to represent the compounds of the invention will generally show only one of the several different tautomers possible. For example, many types of keto groups are known to exist in equilibrium with the corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer of a given compound is depicted, and whichever is the most prevalent, all tautomers of a given formula are intended.

The atoms making up the compounds of this invention are intended to include all isotopic forms of said atoms. Compounds of the present invention include those in which one or more atoms have been altered or enriched in isotopic abundance, especially those with pharmaceutically acceptable isotopes or those that are useful in pharmaceutical research. Isotopes as used herein include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium, and isotopes of carbon ^{include13C and14C} . Similarly, it is contemplated that one or more carbon atoms of the compounds of the invention may be replaced by silicon atoms. Furthermore, it is contemplated that one or more oxygen atoms of the compounds of the invention may be replaced by one or more sulfur or selenium atoms.

The compounds of the invention may also exist in prodrug form. Because prodrugs are known to enhance numerous desirable drug properties (eg, solubility, bioavailability, manufacturing, etc.), the compounds used in some methods of the invention can be delivered in prodrug form, if desired. Accordingly, the present invention encompasses prodrugs of the compounds of the invention as well as methods of delivering prodrugs. Prodrugs of the compounds used in the present invention can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved to the parent compound during routine manipulation or in vivo. Thus, prodrugs include, for example, compounds described herein wherein a hydroxy, amino or carboxyl group is bonded to any group that cleaves to form a hydroxy, amino or carboxylic acid, respectively, when the prodrug is administered to a subject.

It will be appreciated that the particular anion or cation which forms part of any salt of the invention is not critical so long as the salt as a whole is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and methods for their preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

It is further recognized that the compounds of the present invention include those compounds which have been further modified to contain substituents which are convertible to hydrogen in vivo. This includes those groups that can be converted to a hydrogen atom by enzymatic or chemical means, including but not limited to hydrolysis and hydrogenolysis. Examples include hydrolyzable groups such as acyl groups, groups with oxycarbonyl groups, amino acid residues, peptide residues, o-nitrophenylsulfinyl groups, trimethylsilyl groups, tetrahydropyranyl groups, dihydropyranyl groups, Phenylphosphinyl, etc. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. Examples of groups having an oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl (-C(O)OC(CH ₃ ) ₃ , Boc), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, ethylene Oxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl and the like. Suitable amino acid residues include, but are not limited to, Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine) , Glu (glutamic acid), His (histidine), Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse ( homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine) and β-Ala residues. Examples of suitable amino acid residues also include amino acid residues protected with protecting groups. Examples of suitable protecting groups include those commonly used in peptide synthesis, including acyl (such as formyl and acetyl), arylmethoxycarbonyl (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert- Butoxycarbonyl (-C(O)OC(CH ₃ ) ₃ , Boc) and the like. Suitable peptide residues include those comprising two to five amino acid residues. These amino acid or peptide residues may exist in the stereochemical configuration of D-form, L-form or mixtures thereof. Additionally, amino acid or peptide residues may have asymmetric carbon atoms. Examples of suitable amino acid residues with asymmetric carbon atoms include residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having asymmetric carbon atoms include peptide residues having one or more constituent amino acid residues having asymmetric carbon atoms. Examples of suitable amino acid protecting groups include those commonly used in peptide synthesis, including acyl (such as formyl and acetyl), arylmethoxycarbonyl (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert- Butoxycarbonyl (-C(O)OC(CH ₃ ) ₃ ) and the like. Other examples of substituents "convertible to hydrogen in vivo" include reductively eliminable hydrogenolyzable groups. Examples of suitable reductively eliminable hydrogenolyzable groups include, but are not limited to, arylsulfonyl (e.g. o-toluenesulfonyl); methyl substituted by phenyl or benzyloxy (e.g. benzyl, trityl; and benzyloxymethyl); arylmethoxycarbonyl (such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); and haloethoxycarbonyl (such as β,β,β-trichloroethoxy ylcarbonyl and β-iodoethoxycarbonyl).

The compounds of the present invention may also have the advantage that they may be more effective, less toxic, longer acting and more potent than compounds known in the art, whether used in the indications described herein or in other indications , produce fewer side effects, are more readily absorbed, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance), and/or Compounds known in the art have other useful pharmacological, physical or chemical properties.

III. Biological activity

The results of the assay for the inhibition of IFNγ-induced NO production by several compounds of the present invention are shown in Table 1 below. Below the RAW264.7 heading in the right column of this table, the results are compared to those for bardoxolone methyl (RTA 402, CDDO-Me). Details on this assay are provided in the Examples section below.

Table 1. Inhibition of IFNγ-induced NO production.

IV. Diseases Associated with Inflammation and/or Oxidative Stress

Inflammation is a biological process that provides resistance to infectious or parasitic organisms and repairs damaged tissues. Inflammation is often characterized by local vasodilation, redness, swelling, and pain, recruitment of leukocytes to sites of infection or injury, production of inflammatory cytokines, such as TNF-α and IL-1, and production of reactive oxygen or nitrogen species, such as Hydrogen peroxide, superoxide and peroxynitrite. In later stages of inflammation, tissue remodeling, angiogenesis and scarring (fibrosis) can occur as part of the wound healing process. Under normal circumstances, the inflammatory response is regulated and transient, and resolves in a coordinated fashion once the infection or injury has been adequately addressed. However, if regulatory mechanisms fail, acute inflammation can become excessive and life-threatening. Alternatively, inflammation can become chronic and cause cumulative tissue damage or systemic complications. Based on the evidence presented above, the compounds of the present invention are useful in the treatment or prevention of inflammation or diseases associated with inflammation.

Dysregulation of inflammatory processes is involved in many serious and intractable human diseases, including diseases such as cancer, atherosclerosis and diabetes that are not traditionally considered inflammatory conditions. In the case of cancer, inflammatory processes are associated with tumor formation, progression, metastasis and resistance to therapy. Atherosclerosis, long considered a disorder of lipid metabolism, is now understood as an inflammatory condition in which primarily activated macrophages play an important role in the formation and eventual rupture of atherosclerotic plaques. Activation of inflammatory signaling pathways has also been shown to play a role in the development of insulin resistance and in the peripheral tissue damage associated with diabetic hyperglycemia. Excessive production of reactive oxygen and nitrogen species such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite is a hallmark of inflammatory conditions. Evidence of dysregulated peroxynitrite production has been reported in various diseases (Szabo et al., 2007; Schulz et al., 2008; Forstermann, 2006; Pall, 2007).

Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues resulting from self versus non-self in the immune system Dysfunction of recognition and response mechanisms. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, nerve damage is associated with the activation of microglial cells and e.g. inducible nitric oxide synthase (iNOS) associated with elevated levels of pro-inflammatory proteins. Chronic organ failures such as renal failure, heart failure, liver failure and chronic obstructive pulmonary disease are closely associated with the presence of chronic oxidative stress and inflammation leading to the development of fibrosis and eventual loss of organ function. Oxidative stress in the vascular endothelial cells lining both large and small blood vessels can lead to endothelial dysfunction and is thought to be responsible for systemic cardiovascular disease, complications of diabetes, chronic kidney disease and other forms of organ failure, and many other aspects of aging Important contributors to related diseases, including degenerative diseases of the central nervous system and retina.

Many other conditions involve oxidative stress and inflammation in affected tissues, including inflammatory bowel disease; inflammatory skin disease; mucositis associated with radiation therapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and Various forms of retinopathy; graft failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative conditions of bones and joints, including osteoarthritis and osteoporosis; asthma and cystic fibrosis; episodic disease and neuropsychiatric conditions, including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism-spectrum disorder, and eating disorders such as anorexia nervosa. Dysregulation of inflammatory signaling pathways is thought to be a major factor in the pathologies of muscle wasting diseases including muscular dystrophy and various forms of cachexia.

Dysregulation of inflammatory signaling is also involved in a variety of life-threatening acute conditions, including acute organ failure involving the pancreas, kidneys, liver, or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe burns, and allergies reaction.

Many complications of infectious disease also involve dysregulated inflammatory responses. While an inflammatory response can kill invading pathogens, an excessive inflammatory response can also be quite destructive and in some cases can be a major source of damage in infected tissues. Furthermore, an excessive inflammatory response can also lead to systemic complications due to the overproduction of inflammatory cytokines such as TNF-α and IL-1. This is considered a cause of death from severe influenza, severe acute respiratory syndrome and sepsis.

Aberrant or overexpression of iNOS or cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of many disease processes. For example, it is apparent that NO is a potent mutagen (Tamir and Tannebaum, 1996) and that nitric oxide also activates COX-2 (Salvemini et al., 1994). In addition, iNOS was significantly increased in rat colon tumors induced by the carcinogen azoxymethane (Takahashi et al., 1997). A series of synthetic triterpenoid analogues of oleanolic acid have been shown to be potent inhibitors of cellular inflammatory processes such as induction of nitric oxide synthesis by IFN-γ in mouse macrophages. Induction of enzyme (iNOS) and COX-2. See Honda et al. (2000a); Honda et al. (2000b) and Honda et al. (2002), which are hereby incorporated by reference in their entirety.

In one aspect, compounds disclosed herein are characterized in that they inhibit nitric oxide production induced by exposure to gamma-interferon in macrophage-derived RAW 264.7 cells. They are further characterized by the ability to induce the expression of antioxidant proteins such as NQO1 and reduce the expression of pro-inflammatory proteins such as COX-2 and inducible nitric oxide synthase (iNOS). These properties are relevant for the treatment of a wide variety of diseases and disorders involving oxidative stress and dysregulation of inflammatory processes, including cancer, complications resulting from local or systemic exposure to ionizing radiation, radiation therapy or chemotherapy mucositis, autoimmune disease, cardiovascular disease (including atherosclerosis), ischemia-reperfusion injury, acute and chronic organ failure (including renal failure and heart failure), respiratory disease, diabetes and diabetic complications , severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative disease, eye and retinal disease, acute and chronic pain, degenerative bone disease (including osteoarthritis and osteoporosis), inflammatory bowel disease, dermatitis and Other skin diseases, sepsis, burns, seizures and neuropsychiatric disorders.

Without being bound by theory, it is believed that activation of the antioxidant/anti-inflammatory Keap1/Nrf2/ARE pathway is involved in both the anti-inflammatory and anti-cancer properties of the compounds disclosed herein.

In another aspect, the compounds disclosed herein are useful for treating a subject suffering from a condition resulting from increased levels of oxidative stress in one or more tissues. Oxidative stress results from abnormally high or prolonged levels of reactive oxygen species such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite (formed by the reaction of nitric oxide with superoxide). Oxidative stress can be accompanied by acute or chronic inflammation. Oxidative stress can be caused by: mitochondrial dysfunction, activation of immune cells such as macrophages and neutrophils; transient exposure to external agents, such as ionizing radiation or cytotoxic chemotherapeutic agents (e.g., multiple doxorubicin); trauma or other acute tissue injury; ischemia/reperfusion; poor circulation or anemia; localized or systemic hypoxia or hyperxia; elevated levels of inflammatory cytokines and other Inflammation-related proteins; and/or other abnormal physiological conditions, such as hyperglycemia or hypoglycemia.

Expression of stimulus-inducible heme oxygenase (HO-1), a target gene of the Nrf2 pathway, has been shown to have significant therapeutic effects in animal models of many of these conditions, including myocardial infarction, renal failure, graft failure and Models of rejection, stroke, cardiovascular disease, and autoimmune disease (e.g., Sacerdoti et al., 2005; Abraham and Kappas, 2005; Bach, 2006; Araujo et al., 2003; Liu et al., 2006; Ishikawa et al., 2001 ; Kruger et al., 2006; Satoh et al., 2006; Zhou et al., 2005; Morse and Choi, 2005; Morse and Choi, 2002). This enzyme breaks down free heme into iron, carbon monoxide (CO) and biliverdin (which is then converted into the powerful antioxidant molecule bilirubin).

In another aspect, the compounds of the invention are useful in the prevention or treatment of acute and chronic tissue damage or organ failure resulting from oxidative stress exacerbated by inflammation. Examples of diseases falling into this category include: Examples of diseases falling into this category include heart failure, liver failure, transplant failure and rejection, renal failure, pancreatitis, fibrotic lung disease (especially cystic fibrosis, COPD and Pulmonary fibrosis), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury, glaucoma, stroke, autoimmune disease, autism, macular degeneration, and muscular dystrophy. For example, in the case of autism, studies have shown that increased oxidative stress in the central nervous system can lead to the development of the disease (Chauhan and Chauhan, 2006).

Evidence also links oxidative stress and inflammation to the development and pathology of many other conditions of the central nervous system, including psychiatric conditions, such as psychosis, major depression, and bipolar disorder; seizure disorders, such as epilepsy; pain and sensory syndromes, Examples include migraine, neuropathic pain, or tinnitus; and behavioral syndromes, such as attention deficit disorder. See eg Dickerson et al., 2007; Hanson et al., 2005; Kendall-Tackett, 2007; Lencz et al., 2007; Dudhgaonkar et al., 2006; Lee et al., 2007; Morris et al., 2002; Ruster et al., 2005; McIver et al., 2005; Sarchielli et al., 2006; Kawakami et al., 2006; Ross et al., 2003, all of which are incorporated herein by reference in their entirety. For example, elevated levels of inflammatory cytokines, including TNF, interferon-γ, and IL-6, are associated with severe psychiatric disorders (Dickerson et al., 2007). Microglial activation has also been linked to severe psychiatric disorders. Therefore, downregulation of inflammatory cytokines and inhibition of microglial hyperactivation may benefit patients with schizophrenia, major depression, bipolar disorder, autism spectrum disorder, and other neuropsychiatric conditions.

Thus, in pathologies involving oxidative stress alone or exacerbated by inflammation, treatment may comprise administering to the subject a therapeutically effective amount of a compound of the invention, such as those described above or throughout this specification . Treatment may be administered prophylactically prior to a state of predictable oxidative stress (eg, organ transplantation or administration of radiation therapy to a cancer patient), or therapeutically in contexts involving established oxidative stress and inflammation.

The compounds disclosed herein are broadly applicable in the treatment of inflammatory conditions such as sepsis, dermatitis, autoimmune diseases and osteoarthritis. In one aspect, compounds of the invention are useful in the treatment of inflammatory pain and/or neuropathic pain, eg, by inducing Nrf2 and/or inhibiting NF-κΒ.

In some embodiments, the compounds disclosed herein are useful in the treatment and prevention of diseases such as: cancer, inflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, amyotrophic lateral Cirrhosis, Huntington's disease, autoimmune diseases (such as rheumatoid arthritis, lupus, Crohn's disease, and psoriasis), inflammatory bowel disease, pathogenesis thought to involve a All other diseases of overproduction of nitric oxide or prostaglandins and pathologies involving oxidative stress alone or exacerbated by inflammation.

Another aspect of inflammation is the production of inflammatory prostaglandins, such as prostaglandin E. These molecules promote vasodilation, plasma extravasation, localized pain, elevated temperature and other symptoms of inflammation. Inducible forms of the enzyme COX-2 are associated with their production, and high levels of COX-2 are found in inflamed tissues. Thus, inhibition of COX-2 can reduce many inflammatory symptoms, and many important anti-inflammatory drugs (eg, ibuprofen and celecoxib) work by inhibiting COX-2 activity. However, recent studies have demonstrated that a class of cyclopentenone prostaglandins (cyPGs) (e.g., 15-deoxyprostaglandin J2, aka PGJ2) plays a role in stimulating the coordinated resolution of inflammation (e.g., Rajakariar et al., 2007) . COX-2 is also associated with the production of cyclopentenone prostaglandins. Thus, inhibition of COX-2 may interfere with the complete resolution of inflammation, potentially promoting the persistence of activated immune cells in tissues and leading to chronic "smoldering" inflammation. This effect may lead to an increased incidence of cardiovascular disease in patients taking long-term selective COX-2 inhibitors.

In one aspect, the compounds disclosed herein can be used to control the production of pro-inflammatory cytokines in cells by selectively activating regulatory cysteine residues (RCR) on proteins that regulate the activity of redox-sensitive transcription factors . Activation of the RCR by cyPG has been shown to initiate a pro-digestive program in which the activity of the antioxidant and cytoprotective transcription factor Nrf2 is potently induced and the activity of the pro-oxidative and pro-inflammatory transcription factors NF-κB and STAT is inhibited . In some embodiments, this increases the production of antioxidant and reducing molecules (NQO1, HO-1, SOD1, γ-GCS) and reduces oxidative stress and prooxidative and proinflammatory molecules (iNOS, COX-2 , TNF-α) production. In some embodiments, the compounds of the invention restore cells that host inflammatory events to a non-inflammatory state by promoting the resolution of inflammation and limiting excessive tissue damage to the host.

V. Pharmaceutical Formulations and Routes of Administration

Compounds of the disclosure can be administered by a variety of methods, eg, orally or by injection (eg, subcutaneous, intravenous, intraperitoneal, etc.). Depending on the route of administration, the active compound may be coated with a material to protect the compound from acids and other natural conditions that would inactivate the compound. They can also be administered by continuous perfusion/infusion to the disease or wound site.

To administer a therapeutic compound non-parenterally, it may be necessary to coat the compound with, or co-administer the compound with, a material that prevents its inactivation. For example, therapeutic compounds can be administered to a patient in a suitable carrier such as liposomes or diluents. Pharmaceutically acceptable diluents include saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., 1984).

Therapeutic compounds can also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble), dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. See, eg, U.S. Patent Application entitled "Amorphous Solid Dispersions of CDDO-Me for Delayed Release Oral Dosage Compositions," filed February 13, 2009 by J. Zhang, which is incorporated herein by reference. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions and by using surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (eg, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like). In many cases it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols, such as mannitol and sorbitol, in the compositions. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption (for example, aluminum monostearate or gelatin).

Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield the active ingredient (i.e., therapeutic compound) plus A powder of any additional desired ingredient above.

Therapeutic compounds can be administered orally using, for example, an inert diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or added directly to the subject's diet. For oral therapeutic administration, the therapeutic compound can be incorporated with excipients and used in the following forms: ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers agent etc. Of course, the percentage of therapeutic compound in such compositions and formulations can vary. The amount of therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of a therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the invention are dependent on and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the formulation of the therapeutic compound for the treatment of the desired effect in a patient. limitations inherent in the field of selected disease conditions.

Therapeutic compounds can also be applied topically to the skin, eye or mucous membranes. Alternatively, if local delivery to the lung is desired, the therapeutic compound may be administered by inhalation as a dry powder or aerosol formulation.

The active compounds are administered in a therapeutically effective dose sufficient to treat the condition associated with the patient's condition. For example, the efficacy of compounds can be assessed in animal model systems that are predictive of efficacy in treating human disease, such as those shown in the Examples and Figures.

The actual dosage amount of a compound of the present disclosure or a composition comprising a compound of the present disclosure administered to a subject can be determined by physical and physiological factors such as age, sex, weight, severity of the condition , the type of disease being treated, previous or concurrent therapeutic interventions, idiopathic conditions of the subject and the route of administration. These factors can be determined by those skilled in the art. The administering practitioner will generally determine the concentration of active ingredient in the composition and the appropriate dosage for an individual subject. The dosage can be adjusted by the individual physician if any complications occur.

Effective amounts will generally be in the range of about 0.001 mg/kg to about 1000 mg/kg, about 0.01 mg/kg to about 750 mg/kg, about 100 mg/kg to about 500 mg/kg, about 1.0 mg/kg to about 250 mg/kg, about 10.0 mg/kg to about 150 mg/kg, administered in one or more doses per day for one or several days (depending, of course, on the mode of administration and the factors discussed above). Other suitable dosage ranges include 1 mg to 10000 mg per day, 100 mg to 10000 mg per day, 500 mg to 10000 mg per day, and 500 mg to 1000 mg per day. In some specific embodiments, the amount is less than 10,000 mg/day, ranging from 750 mg to 9000 mg per day.

The effective amount can be less than 1 mg/kg/day, less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day, or less than 10 mg /kg/day. Alternatively, it may range from 1 mg/kg/day to 200 mg/kg/day. For example, with regard to the treatment of diabetic patients, the unit dosage may be an amount that lowers blood glucose by at least 40% compared to untreated subjects. In another embodiment, the unit dose is the amount that lowers blood glucose to a level that is ±10% of the blood glucose level in a non-diabetic subject.

In other non-limiting examples, doses may also include about 1 microgram/kg/body weight, about 5 micrograms/kg/body weight, about 10 micrograms/kg/body weight, about 50 micrograms/kg/body weight, about 100 micrograms/kg/body weight per administration. /kg/body weight, about 200 micrograms/kg/body weight, about 350 micrograms/kg/body weight, about 500 micrograms/kg/body weight, about 1 mg/kg/body weight, about 5 mg/kg/body weight, about 10 mg/kg /body weight, about 50 mg/kg/body weight, about 100 mg/kg/body weight, about 200 mg/kg/body weight, about 350 mg/kg/body weight, about 500 mg/kg/body weight, to about 1000 mg/kg/body weight or higher, and any ranges within it that are exportable. In a non-limiting example of ranges derivable from the numbers set forth herein, about 5 mg/kg body weight to about 100 mg/kg/body weight, about 5 micrograms/kg/body weight to about 500 mg/kg may be administered based on the above numbers /weight range etc.

In certain embodiments, pharmaceutical compositions of the present disclosure may comprise, for example, at least about 0.1% of a compound of the present disclosure. In other embodiments, a compound of the present disclosure may, for example, comprise from about 2% to about 75% or from about 25% to about 60% by weight of the unit, and any range derivable therein.

Single-dose or multiple-dose medicaments are contemplated. The desired time interval for delivering multiple doses can be determined by one skilled in the art using no more than routine experimentation. As an example, a subject may be administered two doses per day about 12 hours apart. In some embodiments, the agent is administered once daily.

The agents can be administered on a regular schedule. A regular schedule as used herein refers to a predetermined specified time period. A regular schedule may cover time periods of the same or different lengths, so long as the schedule is predetermined. For example, a regular schedule could involve twice a day, once a day, every two days, every three days, every four days, every five days, every six days, weekly, monthly, or anything in between Administer on a given number of days or weeks. Alternatively, the predetermined regular schedule may involve twice daily dosing for the first week, then once daily for several months thereafter, and so on. In other embodiments, the present invention provides that the agent may be taken orally and the timing thereof is dependent or independent of food intake. Thus, for example, the medicament may be taken every morning and/or every night, regardless of whether the subject has eaten or is about to eat at that time.

VI. Combination therapy

In addition to being used as monotherapy, the compounds of the invention can also be used in combination therapy. Effective combination therapy can be achieved with a single composition or pharmacological formulation comprising both agents, or with two different compositions or formulations administered simultaneously, wherein one composition comprises a compound of the invention and the other combines The substance comprises a second agent. Alternatively, the therapy may precede or follow treatment with the other agent at intervals ranging from minutes to months.

Non-limiting examples of such combination therapies include one or more compounds of the invention in combination with: another anti-inflammatory agent, a chemotherapeutic agent, radiation therapy, an antidepressant, an antipsychotic, an anticonvulsant, Mood stabilizers, anti-infectives, antihypertensives, cholesterol-lowering or other lipid-regulating agents, agents used to promote weight loss, antithrombotic agents, agents used to treat or prevent cardiovascular events such as myocardial infarction or stroke , antidiabetic agents, agents for reducing transplant rejection or graft versus host disease, antiarthritic agents, analgesics, antiasthmatics or other treatments for respiratory diseases, or agents for treating or preventing skin disorders . The compounds of the invention may be combined with agents designed to improve a patient's immune response to cancer, including, but not limited to, cancer vaccines. See Lu et al. (2011), which is incorporated herein by reference.

VII. Embodiment

The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or a similar result without departing from the spirit and scope of the invention.

Methods and materials

Nitric oxide production and cell viability assays. RAW264.7 mouse macrophages were seeded at 30,000 cells/well in 96-well plates (in triplicate) in RPMI1640+0.5% FBS and incubated at 37°C, 5% CO ₂ incubations. The next day, cells were pretreated with DMSO or drugs (0-200 nM dose range) for 2 hours and then treated with recombinant mouse IFNγ (R&D Systems) for 24 hours. The nitric oxide concentration in the medium was determined using the Griess reagent system (Promega). Cell viability was determined using WST-1 reagent (Roche). _IC50 values were determined based on the inhibition of IFNγ-induced nitric oxide production normalized to cell viability.

NQO1-ARE Luciferase Reporter Assay. This assay allows quantitative evaluation of the endogenous activity of the Nrf2 transcription factor in cultured mammalian cells. Expression of firefly luciferase from the NQO1-ARE luciferase reporter plasmid is controlled by the binding of Nrf2 to a specific enhancer sequence corresponding to that found in the human NADPH:quinone oxidoreductase 1 (NQO1) gene Antioxidant Response Elements (AREs) identified in the promoter region of β (Xie et al., 1995). The plasmid was constructed by inserting the sequence 5′-CAGTCACAGTGACTCAGCAGAATCTG-3′ (SEQ ID NO: 1) covering human NQO1-ARE into pLuc-MCS vector (GenScript Corporation, Piscataway, NJ) using the HindIII/XhoI cloning site. The assay was performed in HuH7 cells maintained in DMEM (Invitrogen) supplemented with 10% FBS and 100 U/ml (each) of penicillin and streptomycin. For the assay, cells were seeded in 96-well plates at 17,000 cells/well. After 24 hours, the cells were co-transfected with 50 ng each of NQO1-ARE reporter plasmid and pRL-TK plasmid using Lipofectamine 2000 transfection reagent (Invitrogen). The pRL-TK plasmid expresses Renilla luciferase constitutively and was used as an internal control to normalize transfection levels. Thirty hours after transfection, the cells were treated with compounds (concentrations ranging from 0 [mu]M to 1 [mu]M) for 18 hours. Firefly and Renilla luciferase activities were determined by Dual-Glo Luciferase Assay (Dual-Glo Luciferase Assay) (Promega, Madison, WI), and the luminescent signal was measured on an L-Max II luminometer (Molecular Devices). Firefly luciferase activity was normalized to Renilla activity and fold induction of normalized firefly activity relative to vehicle control (DMSO) was calculated. The relative potency of compounds to induce Nrf2 transcriptional activity was compared using fold induction at a concentration of 62.5 nM. See Xie et al., 1995, which is incorporated herein by reference.

Synthetic schemes, reagents and yields

plan 1

Reagents and conditions: (a) (COCl) ₂ , DMF (catalyst), CH ₂ Cl ₂ , 0 °C to rt, 2 h; (b) CH ₃ CONHNH ₂ , Et ₃ N, Et ₂ O, 0 °C to rt, 30min, 97%; (c) p-TsOH, toluene, reflux, 1.5h, 74%.

Scenario 2

Reagents and conditions: (a) n-PrCONHNH ₂ , Et ₃ N, CH ₂ Cl ₂ , rt, 2.5h, 98%; (b) p-TsOH, toluene, reflux, 2.5h, 83%.

Option 3

Reagents and conditions: (a) i-PrCONHNH ₂ , Et ₃ N, CH ₂ Cl ₂ , rt, 3h, 91%; (b) p-TsOH, toluene, reflux, 1h, 85%.

Option 4

Reagents and conditions: (a) c-PrCONHNH ₂ , Et ₃ N, CH ₂ Cl ₂ , rt, 3.5h, 86%; (b) p-TsOH, toluene, reflux, 2.5h, 83%.

Option 5

Reagents and conditions: (a) CH ₃ OCH ₂ CONHNH ₂ , Et ₃ N, CH ₂ Cl ₂ , rt, 3.5h, 86%; (b) p-TsOH, toluene, reflux, 1h, 56%.

Option 6

Reagents and conditions: (a) CHONHNH ₂ , Et ₃ N, CH ₂ Cl ₂ , rt, 1.5h, 48%; (b) p-TsOH, toluene, reflux, 1h, 49%.

Option 7

Reagents and conditions: (a) acetamide oxime, Et ₃ N, CH ₂ Cl ₂ , rt, 5h, 93%; (b) toluene, microwave, reflux, 0.5h, 46%.

Option 8

Reagents and conditions: (a) CH ₃ CONH ₂ NH ₂ , EDCI, DMAP, Et ₃ N, CH ₂ Cl ₂ , rt, 17h, 57%; (b) p-TsOH, toluene, microwave, reflux, 1h, 46 %.

Synthesis and Characterization of Compounds and Intermediates

Compound 1: Compound RTA 401 (1.00 g, 2.03 mmol) was dissolved in CH ₂ Cl ₂ (20 mL), and the solution was cooled to 0°C. Oxalyl chloride (0.55 mL, 6.50 mmol) was added followed by DMF (2 drops). The reaction mixture was stirred at room temperature for 2 h, then the reaction mixture was concentrated. The residue was azeotroped _2x with _CH2Cl2 to afford compound 1 as a yellow foam, which was used directly in the next step.

Compound 2: Compound 1 (2.03 mmol) was dissolved in _Et2O (20 mL), and the solution was cooled to 0 °C. A solution of _Et3N (0.565 mL, 4.05 mmol) and acetylhydrazide (226 mg, 3.05 mmol) in _CH2Cl2 ( ₁₀ mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 min, then extracted with EtOAc and washed with water, 1N HCl and water again. The organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound 2 (1.08 g, 97% from RTA 401 ) as an off-white foamy solid: m/z 548.3 (M +1).

Compound TX63384: To a solution of compound 2 (548 mg, 1.00 mmol) in toluene (20 mL) was added p-TsOH (95 mg, 0.50 mmol). The reaction was heated at 135 °C for 1.5 h using an attached Dean-Stark condenser. After cooling to room temperature, the reaction mixture was washed with water, dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to afford compound TX63384 (390 mg, 74%) as an off-white foamy solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ8. 02(s,1H),5.96(s,1H),3.13(m,1H),2.94(d,1H,J=4.5Hz),2.53(s,3H),2.19(m,1H),1.20-2.05 (m,14H),1.45(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),1.06(s,3H),1.05(s,3H),0.95( s, 3H); m/z 530.3 (M+1).

Compound 3: To a solution (5 mL) of butanylhydrazide (156 mg, 1.53 mmol) and Et ₃ N (0.58 mL, 4.16 mmol) in CH ₂ Cl ₂ was added Compound 1 (510 mg, 1.00 mmol) in CH ₂ Cl ₂ solution (5.0 mL). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound 3 (566 mg, 98%) as a white solid: m/z 576.4 (M+1).

Compound TX63475: To a solution of compound 3 (197 mg, 0.342 mmol) in toluene (12 mL) was added p-TsOH (33 mg, 0.174 mmol). The reaction was heated at 135 °C for 2.5 h using an attached Dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc, and washed with saturated NaHCO ₃ and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. Purification of the residue by flash chromatography (silica gel, 100% EtOAc in hexanes) afforded compound TX63475 (159 mg, 83%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H ),5.95(s,1H),3.14(td,1H,J=4.3,13.4Hz),2.94(d,1H,J=4.7Hz),2.81(t,2H,J=7.6Hz),2.19(m ,1H),1.93(m,3H),1.50(m,13H),1.45(s,3H),1.25(s,3H),1.16(s,3H),1.15(s,3H),1.05(s, 3H), 1.04(s, 3H), 0.99(t, 3H, J=7.4Hz), 0.95(s, 3H); m/z 558.4(M+1).

Compound 4: To a solution (5 mL) of isobutyrhydrazide (153 mg, 1.50 mmol) and Et ₃ N (0.58 mL, 4.16 mmol) in CH ₂ Cl ₂ was added Compound 1 (510 mg, 1.00 mmol) in CH ₂ Cl ₂ solution (5.0 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound 4 (525 mg, 91%) as a white solid: m/z 576.4 (M+1).

Compound TX63476: To a solution of compound 4 (282 mg, 0.490 mmol) in toluene (12 mL) was added p-TsOH (48 mg, 0.253 mmol). The reaction was heated at 135 °C for 1 h using an attached Dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc, and washed with saturated NaHCO ₃ and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. Purification of the residue by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) afforded compound TX63476 (233 mg, 85%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 ( s,1H),5.95(s,1H),3.17(m,2H),2.99(d,1H,J=4.7Hz),2.18(dt,1H,J=4.2,14.8Hz),1.90(m,3H ),1.45(m,11H),1.45(s,3H),1.37(d,6H,J＝7.0Hz),1.25(s,3H),1.16(s,3H),1.15(s,3H),1.05 (s,3H), 1.04(s,3H), 0.95(s,3H); m/z 558.3(M+1).

Compound 5: To a solution (5 mL) of cyclopropanecarbohydrazide (155 mg, 1.55 mmol) and Et ₃ N (0.58 mL, 4.16 mmol) in CH ₂ Cl ₂ was added compound 1 (510 mg, 1.00 mmol) in CH ₂ Cl ₂ (5.0 mL). The reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound 5 (495 mg, 86%) as a white solid: m/z 574.3 (M+1).

Compound TX63477: To a solution of compound 5 (288 mg, 0.502 mmol) in toluene (12 mL) was added p-TsOH (55 mg, 0.289 mmol). The reaction was heated at 150 °C for 2.5 h using an attached Dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc, and washed with saturated NaHCO ₃ and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. Purification of the residue by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) afforded compound TX63477 (231 mg, 83%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 ( s,1H),5.95(s,1H),3.10(td,1H,J=3.6,13.2Hz),2.98(d,1H,J=4.7Hz),2.12(m,2H),1.90(m,3H ),1.45(s,3H),1.43(s,15H),1.25(s,3H),1.18(s,3H),1.16(s,3H),1.04(s,3H),1.04(s,3H) , 0.94 (s, 3H); m/z 556.3 (M+1).

Compound 6: To a solution (5 mL) of methoxyacetylhydrazide (166 mg, 1.59 mmol) and Et ₃ N (0.56 mL, 4.02 mmol) in CH ₂ Cl ₂ was added Compound 1 (510 mg, 1.00 mmol) in CH ₂ Cl ₂ (5.0 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound 6 (495 mg, 86%) as a white foam solid: m/z 578.4 (M+1).

Compound TX63478: To a solution of compound 6 (292 mg, 0.505 mmol) in toluene (12 mL) was added p-TsOH (48 mg, 0.253 mmol). The reaction was heated at 150 °C for 1 h using an attached Dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc, and washed with saturated NaHCO ₃ and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. Purification of the residue by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) afforded compound TX63478 (158 mg, 56%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 ( s,1H),5.96(s,1H),4.63(s,2H),3.43(s,3H),3.18(td,1H,J=4.2,13.7Hz),3.01(d,1H,J=4.7Hz ),2.21(m,1H),1.91(m,3H),1.50(m,11H),1.45(s,3H),1.24(s,3H),1.16(s,3H),1.15(s,3H) , 1.05(s,3H), 1.05(s,3H), 0.95(s,3H); m/z 560.3(M+1).

Compound 7: To a solution (5 mL) of formic hydrazide (92 mg, 1.53 mmol) and Et ₃ N (0.56 mL, 4.02 mmol) in CH ₂ Cl ₂ was added compound 1 (510 mg, 1.00 mmol) in CH ₂ Cl ₂ solution (5.0 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound 7 (257 mg, 48%) as a white solid: m/z 534.3 (M+1).

Compound TX63479: To a solution of compound 7 (256 mg, 0.480 mmol) in toluene (12 mL) was added p-TsOH (48 mg, 0.253 mmol). The reaction was heated at 150 °C for 1 h using an attached Dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc, and washed with saturated NaHCO ₃ and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound TX63479 (120 mg, 49%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ8. 36(s, 1H), 8.01(s, 1H), 5.96(s, 1H), 3.20(td, 1H, J=3.8, 13.3 Hz), 2.91(d, 1H, J=4.8 Hz), 2.23(m ,1H),1.93(m,3H),1.46(m,11H),1.44(s,3H),1.25(s,3H),1.15(s,3H),1.14(s,3H),1.06(s, 3H), 1.05(s,3H), 0.96(s,3H); m/z 516.3(M+1).

Compound 8: To a solution (5 mL) of acetamide oxime (113 mg, 1.53 mmol) and Et ₃ N (0.56 mL, 4.02 mmol) in CH ₂ Cl ₂ was added Compound 1 (510 mg, 1.00 mmol) in CH _{2 A} solution of Cl2 (5.0 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was then concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to afford compound 8 (510 mg, 93%) as a white solid: m/z 548.3 (M+1).

Compound TX63501: Compound 8 (27 mg, 0.049 mmol) was dissolved in toluene (1 mL), and the solution was heated by microwave heating at 170°C for 10 min, then at 200°C for 20 min. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by flash chromatography (silica gel, 0% to 80% EtOAc in hexanes) to afford compound TX63501 (12 mg, 46%) as a white solid: ¹ H NMR (400 MHz, CDCl _3. ) δ8 .01(s,1H),5.95(s,1H),3.14(m,1H),3.02(d,1H,J=4.7 Hz),2.21(s,3H),2.14(m,1H),1.93( m,3H),1.50(m,13H),1.45(s,3H),1.25(s,3H),1.18(m,1H),1.16(s,3H),1.15(s,3H),1.04(s ,3H), 0.98(s,3H); m/z 530.3(M+1).

Compound 9: Add acetylhydrazide (18.6 mg, 0.251 mmol _{), Et 3 N} ( ₂₈ μL, 0.201 mmol) and DMAP (24.4 mg, 0.200 mmol). EDCI (40 mg, 0.209 mmol) was then added and the reaction was stirred at room temperature for 17h. The reaction mixture was extracted with EtOAc and washed with saturated 1N HCl and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (silica gel, ₀ % to 10% MeOH in _CH2Cl2 ) to afford compound 9 (33 mg, 57%) as a white solid: m/z 512.3 (M+1).

Compound TX63593: To a solution of compound 9 (25 mg, 0.045 mmol) in toluene (1.5 mL) was added p-TsOH (4.8 mg, 0.025 mmol). The reaction mixture was heated at 125 °C for 1 h by microwave heating. After cooling to room temperature, the reaction mixture was extracted with EtOAc and washed with saturated NaHCO ₃ and brine. The organic extracts _were dried over _Na2SO4 , filtered and concentrated. Purification of the residue by flash chromatography (silica gel, 20% to 100% EtOAc in hexanes) afforded compound TX63593 (11 mg, 46%) as an off-white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 ( s,1H),6.01(s,1H),3.12(d,1H,J=5.0Hz),3.12(d,1H,J=14.1Hz),2.69(d,1H,J=14.5Hz),2.52( s,3H),2.27(m,1H),1.98(m,2H),1.78(m,3H),1.56(m,3H),1.56(s,3H),1.52(s,3H),1.27(s ,3H), 1.19(m,7H), 1.19(s,3H), 1.04(s,3H), 0.91(s,3H), 0.88(s,3H); m/z 544.3(M+1).

All of the compounds, compositions and methods disclosed and claimed herein can be made and performed without undue experimentation in light of the present disclosure. While the present disclosure has been described in terms of only certain embodiments, it will be apparent to those skilled in the art that the compounds, compositions and methods described herein can be modified without departing from the concept, spirit and scope of the invention. As well as the steps or the order of the steps of the method are changed. More specifically, it will be apparent that certain agents, both chemically and physiologically related, may be substituted for those described herein and still achieve the same or similar results. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Claims (12)

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: in: n is 0-3; Ar is heteroaryldiyl _(C≤8) or a substituted form thereof; and Y is: hydrogen, hydroxy, halo, amino or cyano or –NCO; or Alkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤8) , Heterocycloalkyl _(C≤12) , acyl _(C≤12) , alkoxy _(C≤8) , aryloxy _(C≤12) , acyloxy _(C≤8) , alkylamino _{(C≤ 8)} , dialkylamino _(C≤8) , arylamino _(C≤8) , aralkylamino _(C≤8) , alkylthio _(C≤8) , acylthio _(C≤8) , Alkylsulfonylamino _(C≤8) , or substituted forms of any of these groups. 2. The compound of claim 1, wherein Y is -H. 3. The compound according to claim 1, wherein Y is alkyl _(C≤4) . 4. The compound of claim 3, wherein Y is methyl, n-propyl, isopropyl or cyclopropyl. 5. The compound according to claim 1, wherein Y is substituted alkyl _(C≤4) . 6. The compound of claim 5, wherein Y is methoxymethyl. 7. The compound according to any one of claims 1-6, wherein Ar is or 8. The compound according to any one of claims 1-7, wherein n=0. 9. The compound according to any one of claims 1-7, wherein n=1. 10. The compound of claim 1, further defined as: or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising: a) a compound according to any one of claims 1-10; and b) Excipients. 12. A method of treating and/or preventing a disease or disorder in a patient in need thereof, comprising administering to said patient any one of the following compounds according to claims 1-10 compounds mentioned in the item.